Gas-filled microbubbles are a proven contrast agent, a means to enhance ultrasound imaging for medical diagnosis and in particular echocardiograms. They are infused into the bloodstream and, as they pass beneath the transducer, the ultrasound image is brightened and vascular details are revealed due to their echogenic properties. Microbubbles may also be used for therapeutic applications. This includes disruption of bubbles with ultrasound in order to permeabilize tissue and therefore enhance drug uptake and efficacy. This technique has been referred to as acoustic activation, sonoporation, contrast-mediated drug delivery, inertial cavitation and non-inertial cavitation.
A variety of acoustically activated drug delivery systems exist including gas bubbles combined with drugs, drugs encapsulated in microspheres, biodegradable polymer and drug solution gas bubbles, drug impregnated microsponges, injectable nanoparticles such as vesicles, micelles, and liposomes, and other drug carrying particles, bubbles, or spheres that permit acoustic activation of therapeutic agents.
Acoustically activated drug delivery systems are typically administered to a patient and then activated by extracorporeal ultrasound to increase the permeability of cell membranes to allow drugs to better penetrate cells, enhance drug uptake, and hence improve the treatment efficacy.
Acoustic activation may permit localized drug delivery. The physician may apply ultrasound once the drug and cavitation nuclei, typically microbubbles, are delivered to a point of interest within a patient, in order to release the drug at the disease site. Localized drug delivery permits a high dosage of toxic drugs to improve treatment effectiveness and may minimize negative side effects to healthy tissue. Permeabilization of tissue in order to increase drug uptake may or may not be done in combination with localized delivery.
Focused acoustic activation may permit localized drug delivery. The therapeutic agent and microbubbles may be administered systemically within a patient and special Focused ultrasound used to locally sonicate an area of interest, such as a tumour, in order to permeabilize tissue within the disease site. The therapeutic agent may be administered to the brain through the carotid artery and special trans-skull Focused ultrasound used to locally sonicate an area of interest in order to overcome the blood brain barrier and permit effective drug treatment.
Ultrasound energy may cause gas microbubbles to resonate or burst into smaller fragments, and may induce bubble resonance that physically deforms cell membranes, or cavitation, or microstreaming, or the perforation of cell membranes. Bubble resonance is typically described as sonoporation or non-inertial cavitation, while the bubble destruction is described as inertial cavitation.
The therapeutic agents may be chemotherapy drugs, gene therapy, fusion proteins, and other agents.
Direct injection of chemotherapy drugs into tumours is typically not done, as this does not improve patient outcome. Cancers may develop resistance to drugs and render chemotherapy useless. Acoustic activation researchers have destroyed human, drug-resistant tumours in rodents using cavitation nuclei and ultrasound.
Acoustic activation technology shows promise for the treatment of drug resistant cancer tumours, vascular disease, neurological diseases, and other diseases. Efficacy may be enhanced by infusing drugs with bubbles and enhancing cell permeability with ultrasound energy. Further benefits may be obtained by infusing transient gas microbubbles in combination with acoustically activated drug delivery release systems to enhance the local cavitation effects.
Presently, acoustically activated drug delivery systems are typically hard-shelled, persistent, gas microbubbles formulated in a pharmaceutical setting. They are designed to persist through to administration to a patient. Such products are required to maintain integrity through the shock, vibration, and temperature changes of transportation and to persist over time through to administration. Such formulations may include complex design and processing features, for example, are typically lipid, polymer, or polymer and solvent based. However, these persistent systems must also dissipate or degrade in the patient once administered and activated. These polymers and any other components are required to biodegrade with minimal negative side effects.
Acoustically activated drug delivery systems may range in size from nano scale, sub micron, up to 1000 microns, with a one to ten micron size typical. Size preference depends upon the resonant frequency, or a harmonic, of the bubble or particle to be activated at a particular ultrasound frequency, and may also depend upon the desired release rates of the encapsulated drugs. Increased size uniformity would encourage effective and more complete activation.
Acoustic activation techniques include inertial cavitation, where gas microbubbles are destroyed by ultrasound energy and bubble shell fragments perforate cells to create nano sized openings, and non-inertial cavitation or sonoporation, where ultrasound energy causes bubbles to resonate. Researchers have demonstrated in vivo therapeutic enhancement with both techniques. In addition, sonophoresis involves the application of ultrasound, or ultrasound and cavitation nuclei such as microbubbles, to increase the permeability of surface cells, such as the skin or cornea, in order to improve the delivery of topically applied drugs.
In the field of oncology, chemotherapy is typically administered intravenously for systemic treatment. Some localized drug delivery techniques are practised, for example, targeted drugs, shunting techniques to direct a drug through a tumour vasculature, direct ethanol or acid injection for ablation of liver tumours, and interoperative peritoneal techniques including hyperthermic intraoperative peritoneal chemotherapy (HIPEC) where chemotherapy is heated and poured directly into the abdomen during open surgery in order to treat tumours too small to be visually detected.
In terminal cases, drug treatment may be ineffective as the metastasis of the disease causes it to reappear after initial chemotherapy cycles and the debilitating side effects of systemic chemotherapy preclude repeat systemic chemotherapy administration at effective dose levels. As well, a cancer may have inherent or developed drug resistance.
Promising new medicines, in particular gene therapy drugs, may be unsuitable for clinical use due to inadequate delivery techniques and other new drugs may possess unduly high toxicity.
Therefore the following needs exist in oncology: a means to enhance locally improved uptake of chemotherapy in a tumour in order to achieve effective treatment with less dose and toxicity, a means to overcome drug resistance, and a means to effectively deliver new medicines.
Oncologists do not currently have a means to provide patients with a flexible, acoustically activated therapy, i.e. the means to enhance a variety of drugs, or combination of drugs, with improved drug uptake and efficacy and reduced side effects.
High intensity Focused ultrasound (HIFU) is a means to induce cell necrosis in diseased tissue, for example to destroy tumours through heat ablation. Heat ablation probes typically require about fifteen minutes in which to heat up to effective ablation temperatures and a similar cool down period. This duration may preclude treatment if patients are in overall poor health and require a number of tumours to be destroyed, add to the cost and invasiveness of the technique, including anaesthesia requirements. A means to reduce treatment duration is desirable.
In a serious pandemic, effective vaccines may be developed but until sufficient quantities are available medical authorities may be unable to treat all effected patients. A means to maximize the number of patients treated with a limited supply of vaccine would be highly desirable. This could be accomplished through enhanced delivery techniques, for example direct vaccine delivery to the spleen combined with microbubbles and acoustic activation in order use less vaccine dose per patient.
Accordingly, there is a need for medical bubble generating apparatus and processes controllably providing medical bubbles (micro and nano) useful for therapy, sonoporation, inertial and non-inertial cavitation, acoustic activation, targeted delivery and ultrasound imaging, among other medical uses, that have medically desirable and selectable sizes, size distributions, concentrations and homogeneities, among other key bubble parameters.